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Synthetic method of (4S)-N-Boc-4-methoxymethyl-L-proline amine salt

A technology of methoxymethyl and proline amine salt, which is applied in the field of medicine, can solve the problems of high raw material cost and production cost, long reaction route, hidden safety hazards, etc., achieve low raw material cost and production cost, and easy purification and separation , reducing the effect of the reaction step

Active Publication Date: 2016-12-28
上海飞腾医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has the disadvantages of long reaction route, high raw material cost and production cost, difficult purification and low yield.
Or as shown in US20130115194, with (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester as reactant, with (2S)-N-Boc-4-oxopyrrolidine-2-carboxylic acid Methyl ester reaction to obtain (2S)-N-Boc-4-methoxymethylpyrrolidine-2-carboxylic acid methyl ester, followed by hydrogenation reduction and esterolysis reaction to obtain (4S)-N-Boc-4- Methoxymethyl-L-proline, this method has certain potential safety hazards due to the use of diazo compounds

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Synthesis of N-Boc-L-hydroxyproline (IM1):

[0028] In a 2L reaction flask, add 131.13g (1mol) L-hydroxyproline and 500mL water, stir to dissolve, then add about 240g saturated potassium carbonate solution to adjust the pH=8~9. The reaction solution was heated to 20~25°C, and a solution of 218.25g (1mol) (Boc)2O in 500mL THF was added dropwise. After the dropwise addition, keep the temperature at 20~25°C for 18 hours, then distill under reduced pressure to remove THF in the system. The aqueous phase was extracted with 2 x 250 mL methyl tert-butyl ether. Cool the water phase to 0~5°C with an ice-salt bath, adjust the pH to 2~3 with 4N HCl, add solid NaCl to the water phase, extract 3 times with 1.1L ethyl acetate, combine the organic phases, and wash with 300mL saturated brine , liquid separation, the organic phase was dried with anhydrous sodium sulfate for 2h, filtered, and the filtrate was concentrated to obtain an oily substance, which became a white solid after st...

Embodiment 2

[0036] Synthesis of N-Boc-L-hydroxyproline (IM1):

[0037] In a 2L reaction flask, add 131.13g (1mol) L-hydroxyproline and 500mL water, stir to dissolve, then add about 240g saturated potassium carbonate solution to adjust the pH=8~9. The reaction solution was heated to 20~25°C, and a solution of 218.25g (1mol) (Boc)2O in 500mL THF was added dropwise. After the dropwise addition, keep the temperature at 20~25°C for 18 hours, then distill under reduced pressure to remove THF in the system. The aqueous phase was extracted with 2 x 250 mL methyl tert-butyl ether. Cool the water phase to 0~5°C with an ice-salt bath, adjust the pH to 2~3 with 4N HCl, add solid NaCl to the water phase, extract 3 times with 1.1L ethyl acetate, combine the organic phases, and wash with 300mL saturated brine , liquid separation, the organic phase was dried with anhydrous sodium sulfate for 2h, filtered, and the filtrate was concentrated to obtain an oily substance, which became a white solid after st...

Embodiment 3

[0045] Synthesis of N-Boc-L-hydroxyproline (IM1):

[0046] In a 2L reaction flask, add 131.13g (1mol) L-hydroxyproline and 500mL water, stir to dissolve, then add about 240g saturated potassium carbonate solution to adjust the pH=8~9. The reaction solution was heated to 20~25°C, and a solution of 218.25g (1mol) (Boc)2O in 500mL THF was added dropwise. After the dropwise addition, keep the temperature at 20~25°C for 18 hours, then distill under reduced pressure to remove THF in the system. The aqueous phase was extracted with 2 x 250 mL methyl tert-butyl ether. Cool the water phase to 0~5°C with an ice-salt bath, adjust the pH to 2~3 with 4N HCl, add solid NaCl to the water phase, extract 3 times with 1.1L ethyl acetate, combine the organic phases, and wash with 300mL saturated brine , liquid separation, the organic phase was dried with anhydrous sodium sulfate for 2h, filtered, and the filtrate was concentrated to obtain an oily substance, which became a white solid after st...

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PUM

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Abstract

The invention discloses a synthetic method of (4S)-N-Boc-4-methoxymethyl-L-proline amine salt. The method comprises the following steps: a) (2S)-N-Boc-4-methoxyl methylene pyrrolidine-2-carboxylic acid and NR1R2R3 amide are subjected to a reaction to prepare (2S)-N-Boc-4-methoxyl methylene pyrrolidine-2-carboxylic acid amine salt; and b) (2S)-N-Boc-4-methoxyl methylene pyrrolidine-2-carboxylic acid amine salt is subjected to a palladium carbon hydrogen reduction reaction to prepare (4S)-N-Boc-4-methoxymethyl-L-proline amine salt; wherein the R1,R2, and R3 are independently selected from hydrogen and alkyl compounds. Through a salt forming system, the oxidation system efficiency is higher, the product is easily purified and separated, the obtained product has the advantages of high purity and good stability, the raw material cost and production cost are relatively low, no hidden trouble is existed, and the method has the advantages of economic performance and environmental protection.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a synthesis method of (4S)-N-Boc-4-methoxymethyl-L-proline amine salt. Background technique [0002] Hepatitis C virus, referred to as hepatitis C, hepatitis C, is a viral disease caused by hepatitis C virus (Hepatitis C Virus, HCV) infection. After HCV infection, 50%-85% will be transformed into chronic infection. If reasonable prevention and treatment measures are not taken, patients will eventually lead to liver cirrhosis and hepatocellular carcinoma, which seriously threatens life safety. HCV is mainly transmitted through blood, acupuncture and drug abuse. Some data show that the global HCV infection-related mortality (death from liver failure and hepatocellular carcinoma) will continue to increase in the next 20 years, and the prevention and treatment of HCV has become one of the world's major public health problems. [0003] At present, the treatment of hepatitis C i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16C07D207/277C07C211/03C07C211/35C07C211/27C07C211/38C07C209/00C07B53/00
CPCC07B53/00C07B2200/07C07D207/16C07D207/277
Inventor 林文清朱剑平刘小波郑宏杰
Owner 上海飞腾医药科技有限公司
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